Annex 2. Systematic review HIV FS by infant feeding … 2. Systematic review HIV FS by infant feeding practice iii Table of Contents 1 Background 1 2 Purpose

Annex 2. Systematic review HIV FS by infant feeding practice

i

A systematic review of HIV-free survival by feeding practices

From birth to 18 months

T Chetty

KK Naidu

ML Newell

30 January 2010


ii

Systematic review of HIV-free survival by infant feeding practices birth to 18 months

T Chetty1, KK Naidu

2, ML Newell

3

1 Public Health Medicine, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal.

2 Maternal and Child Health, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal.

3 Africa Centre for Health and Population Studies, University of KwaZulu-Natal

Contact address: Dr KK Naidu, c/o UKZN Innovation, University of KwaZulu-Natal, Private Bag 7,

Congella, 4013, KwaZulu-Natal, South Africa. Email: [email protected]


iii

Table of Contents

1 Background.....................................................................................................................................1

2 Purpose ..........................................................................................................................................2

3 Research Question .........................................................................................................................2

3 Methods .........................................................................................................................................4

3.1 Criteria for considering studies for this review.......................................................................4

3.2 Search methods for identification of studies..........................................................................5

3.3 Data collection and analysis....................................................................................................6

4 Results ............................................................................................................................................8

4.1 Study selection........................................................................................................................8

4.2 Study characteristics and risk of bias ......................................................................................9

5 Grade profiles for recommendations.............................................................................................9

6 Discussion.....................................................................................................................................16

7 Contributions of authors ..............................................................................................................18

8 Declaration of interest .................................................................................................................18

9 References………………………………………………………………………………………………………………………………19


1

1 Background

Globally an estimated 33 million (30 million - 36 million) people were living with human

immunodeficiency virus type-1 (HIV) in 2007 [1]. Children less than 15 years old accounted for

approximately 2.0 million (1.9 million - 2.3 million) of those living with HIV with an estimated 370 000

(330 000 - 410 000) children < 15 years newly infected in 2007 [1]. Sub-Saharan Africa is at the core

of the epidemic, home to 90% of the HIV burden worldwide [1].

Vertical transmission of HIV occurs during pregnancy, the birth process, and through breastfeeding

[2-3]. In non-breastfed populations, the combined risk of transmission without any interventions is

15-30% [2]. In breastfed populations, the combined risk of transmission in the absence of

interventions, in populations who practice prolonged breastfeeding is 35%. The risk of continued HIV

transmission through breastfeeding is directly related to the duration of breastfeeding [4]. In

developed countries where a combination of interventions are available, vertical transmission of HIV

occurs in 1-2% of infants born to HIV infected women [5-10]. In Africa, where prolonged

breastfeeding for 18-24 months is commonplace, HIV transmission through breast milk may

contribute a further risk of 10-15% [11-13]

Yet, the benefits of breastfeeding, including provision of immunity against non-HIV related infectious

diseases, have to be balanced against the risk of HIV transmission and the morbidity and mortality

associated with alternative feeding practices [14-17]. According to the World Health Organization

(WHO), formula feeding should only be recommended as an alternative to breastfeeding of HIV-

exposed infants when it is affordable, feasible, acceptable, sustainable and safe (AFASS)[18]. The

WHO criteria are rarely met in developing countries and mixed feeding i.e. a combination of

breastfeeding and replacement feeding is common. Mixed feeding is deleterious to an infant’s health

and chances of survival combining the risk of HIV transmission through breastfeeding with the

increased risk of morbidity associated with formula feeding [19]. Furthermore, infants who receive

mixed feeds are more likely to acquire HIV infection than their exclusively breastfed counterparts

[14].

Recently published evidence has shown that antiretroviral drugs (ARVs), either lifelong antiretroviral

therapy (ART) or antiretroviral drug prophylaxis given either to the breastfeeding mother or the

infant can reduce the risk of breastfeeding transmission. Although these interventions have

demonstrated reduction in the risk of HIV transmission in clinical studies, their effectiveness have not

been evaluated throughout the entire duration of breastfeeding or in programmatic settings. In

populations where both mother and the infant are HIV-uninfected, the protective benefit of


2

breastfeeding with regards to survival reduces after 6-12 months of age. Continued breastfeeding

until 24 months of age is justified by the benefits apart from survival [20]. In HIV-infected

populations, however, shortening the duration of breastfeeding is justifiable because of the risk of

HIV transmission associated with continued breastfeeding. However, the most appropriate time to

stop breastfeeding in order to promote HIV-free survival at 18 months is unclear especially now that

ARV interventions can reduce postnatal transmission. This systematic review assessed the available

evidence to determine whether the protective benefits associated with breastfeeding beyond 6

months of age outweighs the risks of continued breastfeeding with respect to HIV transmission - in

the presence or absence of ARV interventions. The review addressed the potential effectiveness of

breastfeeding with ARV prophylaxis versus replacement feeding alternatives.

2 Purpose

The objective of the systematic review was to pool and evaluate the data on the effectiveness of

different infant feeding practices from birth to 18 months in achieving HIV-free survival of HIV-

exposed infants. Also to determine the risk of death due to non HIV-related infectious diseases and

malnutrition associated with non-breastfeeding of HIV-exposed infants during the same period.

3 Research Question (to be examined through the systematic review)

The following questions were addressed:

1. In infants born to HIV-infected mothers,

Who are on lifelong ART, or

Who are known to have CD4 counts >200, >350 but not on ART, or

Whose CD4 count is unknown,

Does exclusive breastfeeding up to 6 months of life, in the absence/presence of a prophylactic

ARV intervention, compared to mixed breastfeeding / replacement feeding up to 6 months of

life, result in better HIV free survival of the infant at 18 months of age?


3


Who are lifelong ART, or



And who have breastfed for the first 6 months of life, does continued breastfeeding until 12

months of life, in the absence/presence of a prophylactic ARV intervention, compared to

replacement feeding between 6 and 12 months of life result in better HIV free survival of the

infant at 18 months of age?


Who are lifelong ART, or



And who have breastfed for the first 12 months of life, does continued breastfeeding until 18

months of life, in the absence/presence of a prophylactic ARV intervention, compared to

replacement feeding between 12 and 18 months of life result in better HIV free survival of the

infant at 18 months of age?

4. In infants born to HIV-infected mothers and who have been breastfed for some period in the first

months of life, does abrupt cessation of breastfeeding e.g. in 2-3 days compared to cessation of

breastfeeding accomplished over a period of weeks/months result in greater serious morbidity

and mortality in the infant by 12 or 18 months of age?


4

3 Methods

3.1 Criteria for considering studies for this review

Types of studies

Randomized clinical trials assessing the risk of mother-to-child transmission (MTCT) of HIV associated

with different infant feeding practices between birth and 18 months (birth to ~5 months; ~6-11

months; and ~12-18 months) were included in the analysis. The analysis also included other non-

randomized clinical trials and intervention cohorts that provided data on HIV-free survival by

different infant feeding practices. Studies performed in any country were included. Studies not

published in English were excluded from the analysis. Reports published or conference abstracts

presented between January 1998 to October 2009 were eligible for inclusion.

Types of participants

HIV-exposed infants from birth to 18 months

Types of interventions

• Breastfeeding (exclusive, non-exclusive or breastfeeding not categorized) from birth to ~5

months, continued breastfeeding to 12 months or 18 months

• Replacement feeding for any period 0-18 months

No consideration was given to the nature of complimentary feeds given in any period

Types of outcome measures

The following outcomes in HIV-exposed infants were assessed:

Primary outcomes

1. HIV-free survival: infants born to HIV-infected mothers who were alive and uninfected at a given

point in time (for this review HIV-free survival was reviewed, when data was available, at 6 months,

12 months, and 18 months).


5

Secondary outcomes

1. HIV transmission

2. Mortality

3. Morbidity due to non HIV-related infectious diseases

Secondary outcome data were assessed at whatever time points were reported in the manuscripts.

3.2 Search methods for identification of studies

3.2.1 Electronic searches

The following electronic databases were searched:

1. Medline

2. Embase

3. CENTRAL

The authors of the review followed the search strategy as outlined in the Cochrane Reviewers'

Handbook [21] (See search strategy and full protocol in Annex b.).

3.2.2 Searching other resources

Abstracts from the following conferences were searched:

1. 5th

International Aids Conference 2009

2. 4th

South African Aids Conference 2009

3. 16th

Conference on Retroviral and Opportunistic Infections 2009

The authors of the review contacted the relevant experts and authors of recent trials on HIV and

infant feeding to identify other manuscripts due to be soon published and not therefore available

through routine the above databases The search strategy was limited to the English language.


6

3.3 Data collection and analysis

The authors of the study developed the search strategy following the guidelines outlined in the

Cochrane Reviewers' Handbook [21]. Following implementation of the search strategy in the

electronic databases and conference abstracts, the authors selected the relevant studies to be

included in the analysis. The titles of all appropriate abstracts and titles collected from electronic and

hand searches were entered into the Endnote reference software. The titles, abstracts and descriptor

terms of all downloaded material from the electronic search and hand searches were scrutinized;

irrelevant and duplicate texts and articles were discarded. A set of potentially eligible studies were

then selected. Subsequently all abstracts were examined by the authors KKN and TC to determine

relevance; full texts of relevant articles were obtained. When KKN and TC were unsure of the

relevance of a particular abstract then full texts were acquired for full evaluation. There were no

randomized controlled trials specifically addressing the questions posed in this review; observational

studies and trials established for a different purpose but that provided information of relevance to

this review were included.

Selection of studies

KKN and TC independently applied the inclusion criteria in an unblended standardized manner.

Studies were evaluated for relevance according to the protocol namely based on the study design,

types of participants, exposure and outcome measures. Disagreements between the authors were

resolved by consensus. When further information was required to determine the relevance of the

study, authors of the reports were contacted to provide further explanation of the data.

Data extraction and management

The authors of the review, KKN and TC, extracted data using a standardized data extraction form. The

following characteristics were extracted from each included study:

• Type of intervention

• Eligibility criteria for enrolment into the study

• Assessment of risk of bias: study design, sequence generation, allocation

concealment, blinding, loss to follow-up, incomplete outcome data, other

potential bias


7

• Details regarding the study participants: sample size, population

characteristics, country where the study performed, HIV diagnostic testing

utilized and ages when testing performed

• Intervention studied: method of feeding, definition of feeding practice, manner

in which the outcome was collected, frequency and timing of data collection

• Outcome measures: HIV infection status of the child; overall survival; HIV-free

survival birth to ~5 months,~6-11 months, and ~12-18 months; morbidity

Assessment of risk of bias in included studies

Risk of bias was assessed according to the guidelines outlined in the Cochrane Handbook [21].

Studies meeting the inclusion criteria were assessed according to the following:

• Allocation concealment;

• Blinding of intervention;

• Blinding of outcome measurement; and

• Completeness of follow up.

Measures of treatment effect

It was not possible to conduct a meta-analysis for this review due to the heterogeneity of the various

studies in terms of study design, exposures and outcomes.

Assessment of heterogeneity

The studies were assessed with regards to the way outcomes were reported. Thereafter, the

feasibility of pooling study outcomes was assessed in terms of heterogeneity. Pooling of data was

not possible due to the heterogeneity in the various studies in terms of design, methods and

outcome assessment.

Unpublished data

The authors of the study endeavored to identify and include reports that had not yet been published

but that had been submitted or accepted for publication. Where studies as yet unpublished had data


8

that was of relevance to this review, the authors reported the data but did not include it in the

overall results.

4 Results

4.1 Study selection

Initial screening identified 1323 citations; of these, 68 potentially relevant articles were identified.

After reviewing the 68 full text articles, 52 reports (seventeen randomized clinical trials, seventeen

observational prospective cohort studies, and 18 secondary articles that reported outcomes relevant

to this review) met the inclusion criteria for this review (Figure 1 and 2). Eleven studies (12 articles)

reported outcomes according to the feeding modality and were included in the WHO Grading of

Recommendations Assessment, Development and Evaluation (GRADE) profiles.

Figure 1: Electronic databases and conferences searched

SEARCH strategy

Databases

1169 citations

CENTRAL

61

Conference

proceedings

154 citations

1323 citations

All sources

EMBASE

311

SA AIDS

22

IAS

62

MEDLINE

797

CROI

70


9

Figure 2: Flowchart of the screening process

4.2 Study characteristics and risk of bias

The characteristics of each individual study and the risk of bias within the studies are included in the

Evidence summaries (Annex d).

5 Grade profiles for recommendations

The key outcomes from the review were used to populate the WHO GRADE profiles that were

reviewed in the process of revising recommendations [22]. The Grade profiles related to Questions 2

and 3 on continued breastfeeding from 6 to 18 months versus replacement feeding between 6 and

18 months were merged into one grade profile table due to the limited data available for each time

period to address these questions. The relative importance of each outcome were then scored 1-9

on the grade profile table: a score of 7-9 indicated that the outcome was of critical importance, an

outcome scored as 4-6 was important, and an outcome scored as 1-3 was regarded as not important.

593 citations excluded for not

being studies, or for only being

the secondary report of studies

200 duplicates excluded using

Endnote X1 filter for duplicates

362 abstracts excluded for not

meeting the inclusion criteria

16 articles excluded for not

meeting the inclusion criteria

40 articles did not have direct

evidence and were excluded

from the GRADE profiles


10

GRADE Profile 1

Question: In infants born to HIV-infected mothers,

who are lifelong ART, or who are known to have CD4 counts >200, >350 but not on ART, or whose CD4 count is unknown

does exclusive breastfeeding up to 6 months of life, in the absence/presence of a prophylactic ARV intervention,

compared to mixed breastfeeding / replacement feeding up to 6 months of life,

result in better HIV free survival of the infant at 18 months of age?

Settings: Botswana, Cote d'Ivoire, Kenya, South Africa, Zimbabwe

Bibliography: Six studies reported primary data with outcomes by feeding modality and were included in the grade profile (see results of Search strategy in report)

Summary of findings Quality assessment

No of patients Effect

No of studies Design Limitations Inconsistency Indirectness Imprecision Other

considerations

exclusive breastfeeding

up to 6 months of life in

the absence/presence

of a prophylactic ARV

intervention

mixed

breastfeeding/replacement

feeding up to 6 months of life

Relative

(95% CI) Absolute

Quality Importance

HIV free survival of infant 12-24 months MODERATE 9

Mashi [23]

18 months

serious1,2,3

no serious

inconsistency

no serious

indirectness

no serious

imprecision

none 86/483 (84.9%) 80/493 (86.1%)

-5.3 to

2.9% P=0.60

+++

MODERATE

2

randomised

trials Nduati [24]

24 months

serious2,3,4,5

no serious

inconsistency

serious no serious

imprecision

none HIV infections and

deaths

80/197 (40.6%)

58/204 (28.4%) ++

LOW

1

observational

study

VTS [25]

18 months

(n=592)

no serious

limitations

no serious

inconsistency

no serious

indirectness

no serious

imprecision

dose response

gradient 0.75 (95%CI 0.72-0.78) Mixed 0.79 (0.70-0.86)

Replacement 0.80 (0.72-0.87)

+++

MODERATE

HIV transmission 12-24 months MODERATE 9

Mashi [23]

18 months

serious1,2,3

no serious

inconsistency

no serious

indirectness

no serious

imprecision

none 33/493 (6.0%) 53/481 (9.5%)

-6.7 to -

0.5% P=0.02

+++

MODERATE

Nduati [24]

24 months

serious2,3,4,5

no serious

inconsistency

serious no serious

imprecision

none N=142

36.7% (29.4 – 44.0%)

N=128

20.5% (14.0 – 27.0%) P=0.001

++

LOW

3

randomised

trials

ZVITAMBO

[15]

18 months

serious3,6,7

no serious

inconsistency

no serious

indirectness

no serious

imprecision

none n=156

6.94% (2.03 – 12.89%)

n=1414

13.92% (11.63 – 16.26%)

+++

MODERATE

VTS [25]

18 months

no serious

limitations

no serious

inconsistency

no serious

indirectness

no serious

imprecision

dose response

gradient 9.1 cases per 100 child

years

5.8 to

12.5

+++

MODERATE

3

observational

studies DITRAME no serious no serious no serious no serious dose response

2% ( 0.96-0.99) 1% (0.97-1.00) P<0.001 +++


11

PLUS [26]

18 months

limitations inconsistency indirectness imprecision gradient MODERATE

VitA [16]

12 months 0.221 (0.245 – 0.307) 0.333 (0.253 – 0.415)

VitA [16]

15 months

serious7,10

no serious

inconsistency

no serious

indirectness

serious2,3,10

none

0.247 (0.160 -0.344) 0.359 (0.267 – 0.451)

++

LOW

Infant Mortality 12- 24 months

MODERATE

9

Mashi [23] serious1,2,3

no serious

inconsistency

no serious

indirectness

no serious

imprecision

none 62/512 (10.7%) 48/529 (8.5%)

-1.2 to

5.6% P=0.21

+++

MODERATE

2

randomised

trials Nduati [24]

24 months

serious2,3,4,5

no serious

inconsistency

serious no serious

imprecision

none N=114

24.4% (18.2 – 30.7%)

N=121

20.0% (14.4 – 25.6%) P=0.30

++

LOW

1

observational

study

VTS [25]

18 months

N=592

no serious

limitations

no serious

inconsistency

no serious

indirectness

no serious

imprecision

dose response

gradient Exclusive breastfeeding

0.86 (0.83 – 0.88)

Mixed 0.87 (0.78 – 0.93)

Replacement 0.87 (0.78 – 0.92)

+++

MODERATE

1 Post-randomization selection bias

2 Loss to follow up

3 The study was not blinded

4 Non-adherence to assigned intervention

5 Feeding practice not defined

6 Feeding practice not consistent with WHO guidelines

7 Feeding history not detailed well - recall bias

8 Randomization to drug regimen rather than feeding practice

9 Endpoint not stratified by feeding practice

10 Reverse causality


12

GRADE Profile 2.

Note. The Grade profiles related to Questions 2 and 3 on continued breastfeeding from 6 to 18 months versus replacement feeding between 6 and 18 months were merged into one grade profile table (below)

due to the limited data available for each time period to address these questions.

Question: In infants born to HIV-infected mothers,

who are on lifelong ART, or who are known to have CD4 counts >200, >350 but not on ART, or whose CD4 count is unknown, and

who have breastfed for the first 6 months of life

does continued breastfeeding from 6 to 18 months of life, in the absence/presence of a prophylactic ARV intervention,

compared to replacement feeding between 6 and 18 months of life

result in better HIV free survival of the infant at 18 months of age?

Settings: Kenya, Tanzania, Zambia, Zimbabwe

Bibliography: Four studies reported primary data with outcomes by feeding modality and were included in the grade profile (see results of Search strategy in report)



No of

studies Design Limitations Inconsistency Indirectness Imprecision

Other

considerations

breastfeeding from 6 to 18 months of

life, in the absence/presence of a

prophylactic ARV intervention

replacement

feeding between

6 and 18 months

of life

Relative

(95% CI) Absolute

Quality Importance

HIV free survival of infant 12-24 months VERY

LOW 9

ZEBS [27]

24 months

no serious

limitations

no serious

inconsistency

Serious11

no serious

imprecision

none 64% 68.4% P=0.13

++

LOW

2

randomised

trials Nduati [24] serious

2,3,4,5 no serious

inconsistency

Serious11

no serious

imprecision

none 59.4% 71.6%

+

VERY LOW

HIV transmission 12-24 months LOW 9

ZEBS [27] no serious

limitations

no serious

inconsistency

Serious11

no serious

imprecision

none LPNT 6.2% 8.8% P=0.19

++

LOW

MICRO [28]

18 months 33/312 (13.3%) 9.1 –

17.5%

MICRO [28]

24 months

serious2,7

no serious

inconsistency

no serious

indirectness

no serious

imprecision

none

37/312 (17.9%)

11.2 –

24.5%

++

LOW

3

randomised

trials

ZVITAMBO

[15]

18 months

serious3,6,7

no serious

inconsistency

no serious

indirectness

no serious

imprecision

none

LPNT 8.5% 5.47 –

11.63%

++

LOW

Infant Mortality 12- 24 months VERY

LOW 9

1

randomised


limitations

no serious

inconsistency

Serious11

no serious

imprecision

none 24.6% 23.9% P=0.96

+

VERY LOW


13

trial


2 Loss to follow up


4 Non-adherence to assigned intervention


6 Feeding practice not consistent with WHO guidelines

7 Feeding history not detailed well - recall bias

8 Randomization to drug regimen rather than feeding practice


10 Reverse causality

11 Indirect evidence


14

GRADE Profile 3.

Question: In infants born to HIV-infected mothers and who have been breastfed for some period in the first months of life,

does abrupt cessation of breastfeeding e.g. in 2-3 days compared to cessation of breastfeeding accomplished over a period of weeks/months

result in greater serious morbidity and mortality in the infant by 12 or 18 months of age?

Setting Botswana, Malawi, Tanzania, Uganda, Zambia

Bibliography: Six studies reported primary data with outcomes by feeding modality and were included in the grade profile. (see results of Search strategy in report)



No of studies Design Limitations Inconsistency Indirectness Imprecision Other

considerations

abrupt cessation of

breastfeeding e.g. in 2-3

days

cessation of breastfeeding

accomplished over a period of

weeks/months

Relative

(95% CI) Absolute

Quality Importance

Infant Mortality 12-24 months MODERATE 9


limitations

no serious

inconsistency

no serious

indirectness

no serious

imprecision

None

23.9% 24.6% (P=0.96). ++++

HIGH

2 randomised

trials

MASHI

[23] serious

1,2,3

no serious

inconsistency

no serious

indirectness

no serious

imprecision None 63/591 (10.7%) 51/588 (8.7%)

++

LOW

MITRA

PLUS [29]

no serious

limitations

no serious

inconsistency

no serious

indirectness

no serious

imprecision

none 37/386 (8.5%) 40/350 (9.2%)

++

LOW

2 observational

studies

HOMSY

[30]

serious2,5,8

no serious

inconsistency

no serious

indirectness

no serious

imprecision

none

13/23 (56.5%) 2/23 (8.7%) ++

LOW

Infant Morbidity 12-24 months MODERATE 8

ZEBS [27]

no serious

limitations

no serious

inconsistency

no serious

indirectness

no serious

imprecision

None

risk of diarrhoea Greater in weaned group 2.3 – 4.0 3

++++

HIGH

MASHI

[23]

serious1,2,3

no serious

inconsistency

no serious

indirectness

no serious

imprecision

None

Hospitalization

20.3% 15.6% P=0.04

++

LOW

3 randomised

trials

PEPI [31-

32]

serious4,5,6

no serious

inconsistency

no serious

indirectness

no serious

imprecision

None

Frequency of reported

gastroenteritis

(weaning at 6 months)

7 weeks–3 months: 1.6%

(25/1635)

4-6 months: 4.1% (63/1546)

7-9 months: 9.0% (129/1427)

++

LOW

1

observational

studies

NVAZ [32-

33]

serious1,7

no serious

inconsistency

no serious

indirectness

no serious

imprecision

none Frequency of reported

gastroenteritis

7 weeks – 3 months: 1.9%

(25/1302)

4-6 months: 6.4% (79/1239)

+++

VERY LOW


15

7-9 months: 9.2% (107/1168)


2 Loss to follow up



5 Collection of feeding data not detailed

6 Randomized according to drug regimen not feeding practice


8 Confounders not adjusted for - socio-demographics and infant birth weight


16

6 Discussion

The findings of this review were formulated as GRADE profiles and presented at a meeting to review

the World Health Organization recommendations on HIV and infant feeding meeting. The review

summarized the evidence of the impact of breastfeeding or replacement feeding of infants born to

HIV-infected women in terms of HIV-free survival at 18 months in settings.

The review assessed that the quality of the evidence available on each of the four 'research'

questions (section 3) was only of moderate to low quality. This is distinct from the quality of the

studies themselves and their implementation but reflects some limitation of the data when applied

to these exact questions e.g. indirectness (data was not primarily collected for this purpose),

imprecision (small sample size), inconsistency (variance between results of studies) or another study

design limitation.

The review found that there was:

i. moderate quality evidence to support exclusive breastfeeding up to 6 months compared to

replacement feeding or mixed feeding [15-16, 23-26],

ii. low to very low grade evidence to support continued breastfeeding for 6 to12 months and 12

to 24 months respectively [15, 25, 27-28], and

iii. moderate quality evidence that abrupt cessation of breastfeeding or weaning had adverse

health outcomes in terms of morbidity and mortality between 12 to 24 months of life [23, 27,

29-31, 33].

See detailed Grade profiles - Annex d.

Although the quality of evidence supporting the continuation of breastfeeding after 6 months was of

low to moderate quality, the significance of this findings should be considered along side the

evidence on antiretroviral interventions to reduce postnatal transmission of HIV and also the survival

and other benefits of breastfeeding in HIV unexposed infants. These interventions have been shown

to reduce postnatal transmission of HIV to the infant either through the use of prophylactic

antiretrovirals given antenatally to mothers and continued throughout the duration of breast feeding

[29, 34-35], or the use of maternal prophylaxis and extended nevirapine prophylaxis to the infant [31,

36].


17

The strength of the systematic review lies in the application of an objective methodology to search

and capture evidence from reported studies. In this review, the GRADE process was adopted to make

“judgments about the quality of the evidence and the strength of recommendations” [22]. The

quality of evidence was ascertained based on the study design, quality, consistency and directness in

an objective manner. The strength of recommendations were then determined by the Guideline

Development Group after being informed by the systematic reviews.

The studies included in the systematic review, although conducted in developing countries, were

usually conducted in research settings, may not have been established to address the questions of

interest to this review and may not therefore be generalizable to all other settings. The main

limitation of the systematic review was that the patient population, study design, intervention

studied and the outcome in terms of HIV-free survival were not the same across the studies. Hence,

data from the individual studies could not be combined f and a meta-analysis could not be

undertaken. Moreover, although several investigators were contacted by the authors, only one

study that had been accepted for publication but was not yet in the public domain was included in

the review [29]. There were several limitations of the randomized controlled trials included in the

review. Blinding of participants to feeding method was not possible. Most studies were primarily

designed as drug trials with mode of infant feeding recorded as a secondary exposure.

Randomization by feeding modality was therefore not performed. Of the 17 randomized controlled

trials included in this review, only two randomized according to feeding duration or method [24, 27].

Methodological issues may have influenced the outcomes reported in observational studies of infant

feeding and HIV free survival; poor attrition rates, inconsistency in the definition of feeding variables

with WHO guidelines, recall bias with inadequate specification of the pattern and duration of infant

feeding, and variable quality of the studies.

In the context HIV the decision on which infant feeding practice provides greatest benefit is complex.

The protective benefits of exclusive breastfeeding to child survival have to be balanced against the

risk of HIV transmission through breastfeeding and the advantage of avoidance of all HIV

transmission risk associated with replacement feeds needs to be balanced with the increased risk of

non-HIV related infections and death associated with non-breastfeeding, in particular, diarrhea,

pneumonia and malnutrition [14-17]. Moreover, the choice of which feeding modality might be best

for any individual mother and her infant is marred by confusion among health care providers and

counselors about HIV and the most appropriate infant feeding choice [37-39]. The difficulty of

implementing infant feeding guidelines is further complicated by cultural norms and other social

expectations. This consequences of these dilemmas were illustrated in South Africa where, despite


18

intense support and counseling being available to support either exclusive breastfeeding or

replacement feeding, inappropriate feeding practices were common with resulting increased

mortality [25].

Finally, although there is strong evidence for HIV-infected women to exclusively breastfeed for 6

months, the decision on continued breastfeeding remains unclear and further evidence is required.

Very limited data was identified through this review to specifically inform this issue. Although new

interventions exist to reduce the postnatal transmission of HIV through breastfeeding and may

provide opportunity for more safely continuing to breastfeed after 6 months versus, the studies that

are assessing the use of prophylactic antiretroviral therapy throughout the entire duration of

breastfeeding are not yet close to reporting their findings.

7 Contributions of authors

T Chetty wrote the protocol, screened citations, selected and reviewed the studies for inclusion in

the review and the grade profiles, assessed characteristics and the risk of bias of included studies,

revised the grade profiles and wrote the report. KK Naidu contributed to the development of the

protocol, screened abstracts, selected and reviewed studies for inclusion in the review, developed

and revised the grade profiles, assessed the characteristics and risk of bias of included studies, and

edited and reviewed the report. ML Newell contributed to the protocol design, reviewed and

assessed characteristics and the risk of bias of included studies, and reviewed and edited the report

8 Declaration of interest

None


19

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Documents

Annex 2. Systematic review HIV FS by infant feeding … 2. Systematic review HIV FS by infant feeding practice iii Table of Contents 1 Background 1 2 Purpose